Biallelic Mutation of ARHGEF18, Involved in the Determination of Epithelial Apicobasal Polarity, Causes Adult-Onset Retinal Degeneration

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• 作者：Gavin Arno¹ ; ² ; Keren J. Carss³ ; ⁴ ; Sarah Hull¹ ; ² ; Ceniz Zihni¹ ; Anthony G. Robson¹ ; ² ; Alessia Fiorentino¹ ; UK Inherited Retinal Disease Consortium Graeme Black ; Georgina Hall ; Stuart Ingram ; Rachel Gillespie ; Forbes Manson ; Panagiotis Sergouniotis ; Chris Inglehearn ; Carmel Toomes ; Manir Ali ; Martin McKibbin ; James Poulter ; Kamron Khan ; Emma Lord ; Andrea Nemeth ; Susan Downes ; Stephanie Halford ; Jing Yu ; Stefano Lise ; Gavin Arno ; Alessia Fiorentino ; Nikos Ponitkos ; Vincent Plagnol ; Michel Michaelides ; Alison J. Hardcastle ; Michael E. Cheetham ; Andrew R. Webster ; Veronica van Heyningen
• 关键词：retinitis pigmentosa ; inherited retinal dystrophy ; retinal degeneration ; ARHGEF18 ; p114RhoGEF ; apicobasal polarity
• 刊名：The American Journal of Human Genetics
• 出版年：2017
• 出版时间：2 February 2017
• 年：2017
• 卷：100
• 期：2
• 页码：334-342
• 全文大小：1695 K
• 卷排序：100

文摘

Mutations in more than 250 genes are implicated in inherited retinal dystrophy; the encoded proteins are involved in a broad spectrum of pathways. The presence of unsolved families after highly parallel sequencing strategies suggests that further genes remain to be identified. Whole-exome and -genome sequencing studies employed here in large cohorts of affected individuals revealed biallelic mutations in ARHGEF18 in three such individuals. ARHGEF18 encodes ARHGEF18, a guanine nucleotide exchange factor that activates RHOA, a small GTPase protein that is a key component of tight junctions and adherens junctions. This biological pathway is known to be important for retinal development and function, as mutation of CRB1, encoding another component, causes retinal dystrophy. The retinal structure in individuals with ARHGEF18 mutations resembled that seen in subjects with CRB1 mutations. Five mutations were found on six alleles in the three individuals: c.808A>G (p.Thr270Ala), c.1617+5G>A (p.Asp540Glyfs∗63), c.1996C>T (p.Arg666∗), c.2632G>T (p.Glu878∗), and c.2738_2761del (p.Arg913_Glu920del). Functional tests suggest that each disease genotype might retain some ARHGEF18 activity, such that the phenotype described here is not the consequence of nullizygosity. In particular, the p.Thr270Ala missense variant affects a highly conserved residue in the DBL homology domain, which is required for the interaction and activation of RHOA. Previously, knock-out of Arhgef18 in the medaka fish has been shown to cause larval lethality which is preceded by retinal defects that resemble those seen in zebrafish Crumbs complex knock-outs. The findings described here emphasize the peculiar sensitivity of the retina to perturbations of this pathway, which is highlighted as a target for potential therapeutic strategies.